Low serum cobalamin (vitamin B12) levels occur in millions of Americans, especially the elderly. The causes of the mild deficiency state that most of these low levels represent remain poorly understood. Indeed, the underlying cause is often unknown. Moreover, the mechanism of the most common of the known causes, malabsorption due to inadequate splitting of cobalamin from food, is poorly understood. Two areas of research are proposed: establishing that mild transcobalamin I (TC I) deficiency is a common cause of currently unexplained low cobalamin levels and characterizing the genetic defect or other mechanisms responsible for it; and defining the underlying mechanisms of food-cobalamin malabsorption and its possible treatment. Classical TC I deficiency (TC I is a ubiquitous cobalamin-binding protein whose role is unknown) causes low cobalamin levels without causing actual deficiency, but in some cases neurologic dysfunction has been noted. The more common, milder variant may be responsible for many of the 25% of low cobalamin levels that do not produce deficiency, or may, together with coexisting disorders, cause mild deficiency. About 2000 low-cobalamin sera and 1000 low-normal cobalamin sera from several sources will be screened by radioimmunoassay. Subjects found to have low TC I levels will be studied to categorize the expression of their TC I deficiency in blood, saliva and white blood cells, define their cobalamin status by metabolic tests, examine their neurologic status clinically and electrophysiologically, look for coexisting cobalamin disorders, and conduct family studies. Equally important, DNA will be extracted from available material from patients with the rare complete TC I deficiency and their genomic defect(s) will be characterized; the same will be done with cellular DNA from any patients identified in the future. Since more than one defect has already been uncovered, further studies will explore potential posttranslational defects. This will define the underlying mechanisms of TC I deficiency and may also provide diagnostic tests. In the other area of research, gastric status will be defined by biopsy and studies of gastric juice in 40 subjects with food-cobalamin malabsorption, compared with 20 controls with normal absorption. The effect of antibiotics and anti-H. pylori treatment on the malabsorption and on gastric status will be studied also. The mechanisms whereby H. pylori produces food-cobalamin malabsorption will be examined. In addition to the insights to be obtained, it is anticipated that a practical treatment for this common disorder will be established.